Hypothyroid symptoms despite adequate replacement therapy are common, and weight gain is one of the most frequently reported, negatively affecting quality of life. Combination therapy liothyronine/levothyroxine attempts to mimic the endogenous production of thyroid hormone have generated mixed results, mostly because of underpowered and not optimally designed studies. In this proposal we aim to study in detail patients undergoing total thyroidectomy before, and for a six-month period following the procedure while on levothyroxine only or on liothyronine/levothyroxine replacement therapy. We hypothesize that combination liothyronine/levothyroxine when compared to levothyroxine alone will minimize post- thyroidectomy weight gain and prevent the cardiovascular and lipid metabolism dysfunction associated with hypothyroidism. Post-surgical hypothyroidism is a unique experimental model to assess the metabolic effects of hypothyroidism and to compare different therapeutic schemes because: 1) patients can be studied before the procedure in a state of euthyroidism, 2) the onset of hypothyroidism is well defined hence its effects can be clearly defined, and 3) there is no residual endogenous production of thyroid hormone, as compared to autoimmune thyroid disease. These factors eliminate a significant amount of confounders, increasing the internal validity of the proposed study. Here we propose to conduct a proof-of-concept, controlled, double blind, parallel design study whereby patients with clinical indications to total thyroidectomy will undergo phenotype characterization at baseline before surgery while in a euthyroid state. Following surgery, patients will be randomized to levothyroxine alone (standard of care) or liothyronine/levothyroxine replacement therapy for a six-month period. Patients will undergo phenotype characterization at three and six months following surgery. We will assess body composition, 24-hour energy expenditure by whole room indirect calorimetry, cardiovascular function, and lipid metabolism. Additionally we will gather exploratory data on changes in quality of life and on the modulatory effects of a common polymorphism of the type 2 deiodinase gene which has been associated with differential response to thyroid hormone replacement therapy. Collectively, the data obtained from this proof-of-concept study will provide solid point estimates of the metabolic effects of post-surgical hypothyroidism and of differential (or lack thereof) response to liothyronine/levothyroxine replacement therapy. This in turn will provide the rationale whether pursuing the study hypotheses in a large intervention trial, and the tools to adequately power it to evaluate the effectiveness of combination therapy in the treatment of hypothyroidism and for the prevention of its effects on energy balance, cardiovascular system, lipid metabolism, and quality of life.